Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model
Impairment of PI3-K/Akt pathway underlies attenuated endothelial function in aorta of type 2 diabetic mouse model
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DOI：
10.1161/01.hyp.0000147559.10261.a7
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发表时间：
2004-12-01
期刊：
影响因子：
8.3
通讯作者：
Kamata, K
中科院分区：
文献类型：
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作者：
Kobayashi, T;Taguchi, K;Kamata, K
磷脂酰肌醇3-激酶（PI 3-K）途径激活丝氨酸/苏氨酸蛋白激酶Akt，增强内皮型一氧化氮合酶（eNOS）磷酸化和一氧化氮（NO）产生。我们研究了PI 3-K/Akt通路参与乙酰胆碱（ACh）和可乐定在一种新的2型糖尿病模型（链脲佐菌素+烟酰胺诱导的糖尿病小鼠）的舒张反应。在我们的模型中，血浆葡萄糖和胰岛素水平显著升高，静脉葡萄糖耐量试验显示葡萄糖耐量和胰岛素反应性明显异常。虽然在我们的模型中，ACh诱导的舒张和NOx-（NO2- + NO3-）/cGMP的产生没有变化，可乐定和胰岛素诱导的舒张和NOx-/cGMP的产生都大大减弱。在对照组小鼠中，可乐定诱导的和胰岛素诱导的舒张作用分别被LY 294002和Wortmannin（PI 3-K抑制剂）以及Akt抑制剂处理所消除。乙酰胆碱诱导的松弛不受任何一组小鼠的这种治疗。糖尿病小鼠主动脉总Akt蛋白表达水平显著降低，而PI 3-K γ亚基p85和p110蛋白表达水平无明显变化。在我们的模型中，可乐定通过PI 3-K诱导的Akt的Ser-473磷酸化显著降低，而ACh诱导的则没有。这些结果表明，在这种2型糖尿病模型中，通过PI 3-K/Akt通路介导的舒张反应和NO产生减少。这可能是2型糖尿病中内皮功能障碍（以及由此产生的高血压）的主要原因。
The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase ( eNOS) phosphorylation and nitric oxide ( NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model ( streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NOx- (NO2- + NO3-)/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NOx-/cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110gamma subunits of PI3-K were not. The clonidine- induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction ( and the resulting hypertension) in type 2 diabetes.